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Published online before print November 9, 2004

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0904538

Received for publication September 19, 2004.
Revised October 15, 2004.
Accepted for publication October 17, 2004.

Article

Balance of proliferation and cell death between thyrocytes and myofibroblasts regulates thyroid fibrosis in granulomatous experimental autoimmune thyroiditis (G-EAT)

Kemin Chen ^*@, Yongzhong Wei ^*, Gordon C. Sharp ^*, and Helen Braley-Mullen ^*

Departments of *Internal Medicine and Molecular Microbiology & Immunology, University of Missouri School of Medicine, and VA Research Service, Columbia

^@ To whom correspondence should be addressed. E-mail: Chenk{at}health.missouri.edu.

	Abstract

Severe granulomatous experimental autoimmune thyroiditis (G-EAT), which progresses to fibrosis, is induced in DBA/1 mice by adoptive transfer of mouse thyroglobulin-primed and -activated spleen cells. There is extensive destruction of thyrocytes and inflammatory cell infiltration including T cells, macrophages, neutrophils, and myofibroblasts (myofbs). Suppression of transforming growth factor- (TGF-) and deficiency of interferon- (IFN-) inhibit fibrosis, and inflammation eventually resolves. Thyrocyte destruction in wild-type (WT) mice was a result of apoptosis, as many deoxynucleotide triphosphate nick-end labeling + apoptotic thyrocytes were present in these thyroids. The balance of apoptosis and proliferation between thyrocytes and myofbs may be important factors determining the outcome of inflammation to fibrosis versus resolution. Apoptosis and proliferation in thyrocytes versus myofbs were evaluated by dual-staining of cell-proliferating marker (K_i-67) or in situ cell death and cytokeratin or -smooth muscle actin and were analyzed by confocal microscopy. Apoptotic and antiapoptotic molecules in G-EAT thyroids were detected by immunostaining. In WT thyroids, which develop fibrosis, only a few myofbs were apoptotic, and many myofbs were K_i-67+, Fas-associated death domain protein-like interleukin-1-converting enzyme-like inhibitory protein+, and Bcl-XL+. In contrast, proliferation was predominant on thyrocytes of IFN--/- mice or anti-TGF--treated WT mice. These results indicate that apoptosis of inflammatory cells and regeneration of thyrocytes in IFN--/- mice and anti-TGF--treated WT mice may limit development of fibrosis, whereas excessive proliferation of myofbs and loss of thyrocytes in WT mice may contribute to fibrosis.

Key Words: apoptosis • autoimmune inflammation • collagen • autoimmune diseases

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